Compensatory Evolution and the Origins of Innovations

Cryptic genetic sequences have attenuated effects on phenotypes. In the classic view, relaxed selection allows cryptic genetic diversity to build up across individuals in a population, providing alleles that may later contribute to adaptation when co-opted—e.g., following a mutation increasing expression from a low, attenuated baseline. This view is described, for example, by the metaphor of the spread of a population across a neutral network in genotype space. As an alternative view, consider the fact that most phenotypic traits are affected by multiple sequences, including cryptic ones. Even in a strictly clonal population, the co-option of cryptic sequences at different loci may have different phenotypic effects and offer the population multiple adaptive possibilities. Here, we model the evolution of quantitative phenotypic characters encoded by cryptic sequences and compare the relative contributions of genetic diversity and of variation across sites to the phenotypic potential of a population. We show that most of the phenotypic variation accessible through co-option would exist even in populations with no polymorphism. This is made possible by a history of compensatory evolution, whereby the phenotypic effect of a cryptic mutation at one site was balanced by mutations elsewhere in the genome, leading to a diversity of cryptic effect sizes across sites rather than across individuals. Cryptic sequences might accelerate adaptation and facilitate large phenotypic changes even in the absence of genetic diversity, as traditionally defined in terms of alternative alleles.     

A chance at survival: gene expression noise and phenotypic diversification strategies

Phenotypic diversification plays a central role in evolution and provides species with a capacity to survive environmental adversity. The profound impact of random molecular events on the shaping of life is well accepted in the context of chance mutations and genetic drift; however, the evolution of the regulatory networks encoding microorganismal stress response and survival strategies might also have been significantly influenced by gene expression noise. This likelihood has inspired numerous investigations to characterize the sources of phenotypic diversity within isogenic populations, and to explore their direct and potential biological implications. Here, we discuss different scenarios where gene expression noise might bestow a selective advantage under stress, highlighting a potentially fundamental role of stochastic mechanisms in the evolution of microbial survival strategies.     

表型可塑性与外来植物的入侵能力

外来植物的入侵能力与其性状之间的关系是入侵生态学中的基本问题之一。成功的入侵种常常能占据多样化的生境,并以广幅的环境耐受性为特征。遗传分化(包括生态型分化)和表型可塑性是广布性物种适应变化、异质性生境的两种不同但并不矛盾和排斥的策略。越来越多的实验证据表明,表型可塑性具有确定的遗传基础,本身是一种可以独立进化的性状。许多入侵种遗传多样性比较低,但同时又占据了广阔的地理分布区和多样化的生境,表型可塑性可能在这些物种的入侵成功和随后的扩散中起到了关键作用。本文首先介绍表型可塑性的含义,简述表型可塑性和生物适应的关系,然后从理论分析和实验证据两个方面论述了表型可塑性与外来植物入侵能力的相关性,最后针对进一步的研究工作进行了讨论。当然,并非所有入侵种的成功都能归因于表型可塑性,作者认为对于那些遗传多样性比较低同时又占据多样化生境的入侵种,表型可塑性和入侵能力的正相关可能是一条普遍法则,而非特例。     

Testing the molecular and evolutionary causes of a 'leapfrog' pattern of geographical variation in coloration

Understanding the mechanisms accounting for the evolution of phenotypic diversity is central to evolutionary biology. We use molecular and phenotypic data to test hypotheses for 'leapfrog' patterns of geographical variation, in which phenotypically similar, disjunct populations are separated by distinct populations of the same species. Phylogenetic reconstructions revealed independent evolution of melanic plumage characters in different populations in the Neotropical avian genus Arremon. Thus, phenotypic similarities between distant populations cannot be explained by close phylogenetic affinity. Nor can they be attributed to recurring mutations in the MC1R gene, a locus involved in melanic pigmentation. A coalescent analysis indicates that plumage traits have become fixed at a faster rate than expected under genetic drift, suggesting that selection underlies their repeated evolution. In contrast to views that genetic drift drives phenotypic differentiation in Neotropical montane birds, our results imply that geographical variation preceding speciation may reflect the action of deterministic selective processes.     

Implications of disease-related mutations at protein–protein interfaces

Protein–protein interfaces have been attracting great attention owing to their critical roles in protein–protein interactions and the fact that human disease-related mutations are generally enriched in them. Recently, substantial research progress has been made in this field, which has significantly promoted the understanding and treatment of various human diseases. For example, many studies have discovered the properties of disease-related mutations. Besides, as more large-scale experimental data become available, various computational approaches have been proposed to advance our understanding of disease mutations from the data. Here, we overview recent advances in characteristics of disease-related mutations at protein–protein interfaces, mutation effects on protein interactions, and investigation of mutations on specific diseases.     

Integrating genetic and environmental forces that shape the evolution of geographic variation in a marine snail

Temporal and spatial patterns of phenotypic variation have traditionally been thought to reflect genetic differentiation produced by natural selection. Recently, however, there has been growing interest in how natural selection may shape the genetics of phenotypic plasticity to produce patterns of geographic variation and phenotypic evolution. Because the covariance between genetic and environmental influences can modulate the expression of phenotypic variation, a complete understanding of geographic variation requires determining whether these influences covary in the same (cogradient variation) or in opposing (countergradient variation) directions. We focus on marine snails from rocky intertidal shores as an ideal system to explore how genetic and plastic influences contribute to geographic and historical patterns of phenotypic variation. Phenotypic plasticity in response to predator cues, wave action, and water temperature appear to exert a strong influence on small and large-scale morphological variation in marine snails. In particular, plasticity in snail shell thickness: (i) may contribute to phenotypic evolution, (ii) appears to have evolved across small and large spatial scales, and (iii) may be driven by life history trade-offs tied to architectural constraints imposed by the shell. The plasticity exhibited by these snails represents an important adaptive strategy to the pronounced heterogeneity of the intertidal zone and undoubtedly has played a key role in their evolution.     

Genetic constraints on protein evolution

Evolution requires the generation and optimization of new traits ("adaptation") and involves the selection of mutations that improve cellular function. These mutations were assumed to arise by selection of neutral mutations present at all times in the population. Here we review recent evidence that indicates that deleterious mutations are more frequent in the population than previously recognized and that these mutations play a significant role in protein evolution through continuous positive selection. Positively selected mutations include adaptive mutations, i.e. mutations that directly affect enzymatic function, and compensatory mutations, which suppress the pleiotropic effects of adaptive mutations. Compensatory mutations are by far the most frequent of the two and would allow potentially adaptive but deleterious mutations to persist long enough in the population to be positively selected during episodes of adaptation. Compensatory mutations are, by definition, context-dependent and thus constrain the paths available for evolution. This provides a mechanistic basis for the examples of highly constrained evolutionary landscapes and parallel evolution reported in natural and experimental populations. The present review article describes these recent advances in the field of protein evolution and discusses their implications for understanding the genetic basis of disease and for protein engineering in vitro.     

杨属遗传多样性研究进展

 生物多样性的研究和保护是目前全世界普遍关注的问题,其中研究较多的是遗传多样性、物种多样性及生态系统多样性,遗传多样性作为生物多样性的重要组成部分,是生态系统多样性和物种多样性的基础方面。杨树是世界各国普遍种植的木本植物,研究其遗传多样性具有重要的理论和实践意义,国内外都开展了广泛研究。本文综述了杨属(Populus)植物的派、种及无性系等在表型、染色体、蛋白质及DNA水平的遗传多样性的研究进展。其表型多样性主要体现在不同水平上的种群大小、形态特征、物候期、材性以及对生物或非生物逆境的抗性等方面;在杨属植物中已发现有天然的三倍体及三倍体/非整倍体的杂交种存在;蛋白质的多态性主要集中于同工酶的研究,用于不同杨属植物的遗传差异,无性系或品种的特征、分化和遗传研究;DNA多态性是研究最多的,RFLP、RAPD、AFLP和SSR等分子标记已广泛用于杨属的遗传多样性研究中,根据不同的研究目的所选择的DNA（nDNA, cpDNA或mtDNA）也不同。并根据国内的研究现状,提出了几点建议。     

A Dynamic Network Approach for the Study of Human Phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.     

Genetic modifiers of muscular dystrophy: implications for therapy

The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different "private" mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.     

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20?years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.     

Genetics, development and evolution of adaptive pigmentation in vertebrates

The study of pigmentation has played an important role in the intersection of evolution, genetics, and developmental biology. Pigmentation's utility as a visible phenotypic marker has resulted in over 100 years of intense study of coat color mutations in laboratory mice, thereby creating an impressive list of candidate genes and an understanding of the developmental mechanisms responsible for the phenotypic effects. Variation in color and pigment patterning has also served as the focus of many classic studies of naturally occurring phenotypic variation in a wide variety of vertebrates, providing some of the most compelling cases for parallel and convergent evolution. Thus, the pigmentation model system holds much promise for understanding the nature of adaptation by linking genetic changes to variation in fitness-related traits. Here, I first discuss the historical role of pigmentation in genetics, development and evolutionary biology. I then discuss recent empirically based studies in vertebrates, which rely on these historical foundations to make connections between genotype and phenotype for ecologically important pigmentation traits. These studies provide insight into the evolutionary process by uncovering the genetic basis of adaptive traits and addressing such long-standing questions in evolutionary biology as (1) are adaptive changes predominantly caused by mutations in regulatory regions or coding regions? (2) is adaptation driven by the fixation of dominant mutations? and (3) to what extent are parallel phenotypic changes caused by similar genetic changes? It is clear that coloration has much to teach us about the molecular basis of organismal diversity, adaptation and the evolutionary process.     

Mitochondrial DNA mutations and human disease

Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of mitochondrial genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances.     

MODELING PHENOTYPIC PLASTICITY IN GROWTH TRAJECTORIES: A STATISTICAL FRAMEWORK

Phenotypic plasticity, that is multiple phenotypes produced by a single genotype in response to environmental change, has been thought to play an important role in evolution and speciation. Historically, knowledge about phenotypic plasticity has resulted from the analysis of static traits measured at a single time point. New insight into the adaptive nature of plasticity can be gained by an understanding of how organisms alter their developmental processes in a range of environments. Recent advances in statistical modeling of functional data and developmental genetics allow us to construct a dynamic framework of plastic response in developmental form and pattern. Under this framework, development, genetics, and evolution can be synthesized through statistical bridges to better address how evolution results from phenotypic variation in the process of development via genetic alterations.     

Patterns of introduction and diversification of Vanilla planifolia (Orchidaceae) in Reunion Island (Indian Ocean)

The cultivated species Vanilla planifolia is a typical example of a crop introduced from its area of origin (America) to new regions where natural pollinators are absent. Although the Vanilla cultivars are exclusively vegetatively propagated, a high degree of phenotypic variation is observed among the cultivars in their introduction areas such as Reunion Island. To test several hypotheses explaining this variation-different introduction events, somatic mutations and sexual reproduction (through manual pollination)-we used AFLP markers to elucidate the patterns of introduction of V. planifolia. Most of the accessions cultivated in the world were derived from a single accession, possibly the Mexican cultivar Mansa. The patterns of diversification of this cultivated species were also studied and compared with other cultivated (V. tahitensis) and wild (V. pompona and V. bahiana) species. Except for one particular phenotype ('Aiguille'), which may come from sexual reproduction, cultivated accessions exhibit very low levels of genetic diversity. They have evolved by the accumulation of point mutations through vegetative multiplication. The genetic diversity revealed could not explain the phenotypic diversity, which may be related to epigenetics or polyploidy. This new understanding of the basis of genetic diversity of vanilla may assist to improve management of genetic resources.     

From micro- to macroevolution: brood parasitism as a driver of phenotypic diversity in birds

A fundamental question in biology is how diversity evolves and why some clades are more diverse than others. Phenotypic diversity has often been shown to result from morphological adaptation to different habitats. The role of behavioral interactions as a driver of broadscale phenotypic diversity has received comparatively less attention. Behavioral interactions, however, are a key agent of natural selection. Antagonistic behavioral interactions with predators or with parasites can have significant fitness consequences, and hence act as strong evolutionary forces on the phenotype of species, ultimately generating diversity between species of both victims and exploiters. Avian obligate brood parasites lay their eggs in the nests of other species, their hosts, and this behavioral interaction between hosts and parasites is often considered one of the best examples of coevolution in the natural world. In this review, we use the coevolution between brood parasites and their hosts to illustrate the potential of behavioral interactions to drive evolution of phenotypic diversity at different taxonomic scales. We provide a bridge between behavioral ecology and macroevolution by describing how this interaction has increased avian phenotypic diversity not only in the brood parasitic clades but also in their hosts.     

GroEL/S Overexpression Helps to Purge Deleterious Mutations and Reduce Genetic Diversity during Adaptive Protein Evolution

Chaperones are proteins that help other proteins fold. They also affect the adaptive evolution of their client proteins by buffering the effect of deleterious mutations and increasing the genetic diversity of evolving proteins. We study how the bacterial chaperone GroE (GroEL+GroES) affects the evolution of green fluorescent protein (GFP). To this end, we subjected GFP to multiple rounds of mutation and selection for its color phenotype in four replicate Escherichia coli populations, and studied its evolutionary dynamics through high-throughput sequencing and mutant engineering. We evolved GFP both under stabilizing selection for its ancestral (green) phenotype, and to directional selection for a new (cyan) phenotype. We did so both under low and high expression of the chaperone GroE. In contrast to previous work, we observe that GroE does not just buffer but also helps purge deleterious (fluorescence reducing) mutations from evolving populations. In doing so, GroE helps reduce the genetic diversity of evolving populations. In addition, it causes phenotypic heterogeneity in mutants with the same genotype, helping to enhance their fluorescence in some cells, and reducing it in others. Our observations show that chaperones can affect adaptive evolution in more than one way.     

Suppression of premature termination codons as a therapeutic approach

In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.